This invention relates generally to bis-amino acid sulfonamides useful as HIV protease inhibitors, pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as assay standards or reagents.
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion""s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell""s genes and those genes are used for virus reproduction.
At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle""s maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system""s T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system""s effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body""s immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the virus""s life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford et al., J. Virol. 53 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
As evidenced by the protease inhibitors presently marketed and in clinical trials, a wide variety of compounds have been studied as potential HIV protease inhibitors. One core, hydroxyethylamino-sulfonamides, has received significant attention. For example, PCT Applications WO94/05639, WO94/04492, WO95/06030, and WO96/28464 generically describe sulfonamides of the formula: 
and methods of preparing them. Though some of the present compounds appear to fall within the generic descriptions of some of the above publications, they are not specifically disclosed, suggested, or claimed therein.
Even with the current success of protease inhibitors, it has been found that HIV patients can become resistant to a single protease inhibitor. Thus, it is desirable to develop additional protease inhibitors to further combat HIV infection.
Accordingly, one aspect of the present invention is to provide novel protease inhibitors.
The present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
The present invention provides a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
The present invention provides pharmaceutical compositions with protease inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least-one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
The present invention provides a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.
The present invention provides a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV protease, HIV growth, or both.
The present invention provides novel compounds for use in therapy.
The present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of HIV infection.
These and other aspects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
wherein R1, R2, and R3 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective protease inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of Formula I: 
xe2x80x83or a pharmaceutically acceptable salt form thereof, wherein:
R1 is selected from R4 and xe2x80x94Oxe2x80x94R4;
R2 and R3 are selected from H and NH2, or alternatively, R2 and R3 together form xe2x80x94OCH2Oxe2x80x94 or xe2x80x94CH2CH2Oxe2x80x94; and
R4 is selected from methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, phenyl, benzyl, cyclopentyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
[2] In another embodiment, the present invention provides a novel compound of Formula I: wherein
R2 is H; and
R3 is NH2.
[3] In another embodiment, the present invention provides a novel compound of Formula I: wherein
R4 is selected from i-propyl, phenyl, cyclopentyl, 2-pyridyl and 3-pyridyl.
[4] In another embodiment, the present invention provides a novel compound of Formula I, wherein:
R1 is R4; and
R4 is i-propyl.
[5] In another embodiment, the present invention provides a novel compound of Formula I, wherein:
R1 is R4; and
R4 is phenyl, cyclopentyl, 2-pyridyl and 3-pyridyl.
[5] In another embodiment, the present invention provides a novel compound of Formula I, wherein:
R1 is xe2x80x94Oxe2x80x94R4; and
R4 is cyclopentyl.
[7] In another embodiment, the present invention provides a novel compound of Formula II: 
xe2x80x83or a pharmaceutically acceptable salt thereof.
[8] In another embodiment, the present invention provides a novel compound of Formula II, wherein:
R1 is R4; and
R4 is methyl, ethyl, i-propyl, t-butyl, phenyl, and i-butyl.
[9] In another embodiment, the present invention provides a novel compound of Formula II, wherein:
R1 is xe2x80x94Oxe2x80x94R4; and
R4 is methyl, ethyl, i-propyl, cyclopentyl, phenyl, and benzyl.
[10] In another embodiment, the present invention provides a novel compound of Formula III, wherein: 
xe2x80x83or a pharmaceutically acceptable salt thereof.
[11] In another embodiment, the present invention provides a novel compound of Formula III: wherein
R1 is R4; and
R4 is methyl, ethyl, and i-butyl.
[12] In another embodiment, the present invention provides a novel compound of Formula III, wherein:
R1 is xe2x80x94Oxe2x80x94R4; and
R4 is ethyl and i-propyl.
[13] In another embodiment, the present invention provides a novel compound of Formula II, wherein:
R1 is R4; and
R4 is selected from 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
[14] In another embodiment, the present invention provides novel compounds wherein the compound is selected from:
N-[(1-{3-[(4-Amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-nicotinamide;
Pyridine-2-carboxylic acid [(1-{3-[(4-amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-amide;
[(1-{3-[(4-Amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid cyclopentyl ester;
[(1-{1-Benzyl-3-[(2,3-dihydro-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid isopropyl ester;
[(1-{1-Benzyl-3-[(2,3-dihydro-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid ethyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid benzyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid phenyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid phenyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid cyclopentyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid isopropyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid ethyl ester;
[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carbamic acid methyl ester;
N-[(1-{3-[(4-Amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-benzamide;
N-{3-[(4-Amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-2-(2-isobutyrylamino-acetylamino)-3,3-dimethyl-butyramide;
N-{1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-2-(2-isobutyrylamino-acetylamino)-3,3-dimethyl-butyramide;
N-{1-Benzyl-3-[(2,3-dihydro-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-3,3-dimethyl-2-[2-(3-methyl-butyrylamino)-acetylamino]-butyramide;
N-{1-Benzyl-3-[(2,3-dihydro-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-3,3-dimethyl-2-(2-propionylamino-acetylamino)-butyramide;
2-(2-Acetylamino-acetylamino)-N-{1-benzyl-3-[(2,3-dihydro-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-3,3-dimethyl-butyramide;
N-[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-isonicotinamide;
N-[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-nicotinamide;
Pyridine-2-carboxylic acid [(1-{3-[(benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-amide;
4-Amino-N-[(1-{3-[(benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-benzamide;
3-Amino-N-[(1-{3-[(benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-benzamide;
2-Amino-N-[(1-{3-[(benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-benzamide;
2-Amino-N-[(1-{3-[(benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-benzamide;
N-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-3,3-dimethyl-2-[2-(3-methyl-butyrylamino)-acetylamino]-butyramide;
N-[(1-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propylcarbamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-benzamide;
N-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-2-[2-(2,2-dimethyl-propionylamino)-acetylamino]-3,3-dimethyl-butyramide;
N-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-3,3-dimethyl-2-(2-propionylamino-acetylamino)-butyramide;
2-(2-Acetylamino-acetylamino)-N-{3-[(benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-3,3-dimethyl-butyramide; and
N-{3-[(Benzo[1,3]dioxole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-2-(2-isobutyrylamino-acetylamino)-3,3-dimethyl-butyramide.
In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, II or III, or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I, II or III, or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula I, II or III; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another embodiment, the reverse transcriptase inhibitor is selected from the group AZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, ACT, UC-781, UC-782, RD4-2025, and MEN 10979, and the protease inhibitor is selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.
In another embodiment, the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.
In a still other embodiment, the reverse transcriptase inhibitor is AZT.
In another embodiment, the protease inhibitor is ritonavir.
In another embodiment, component (b) is a HIV reverse transcriptase inhibitor and a HIV protease inhibitor.
In another embodiment, component (b) is two different HIV reverse transcriptase inhibitors.
In another embodiment, the present invention provides a pharmaceutical composition useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(a) a compound of formula I, II, or III; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In another embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I, II, or III.
In a ninth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula I, II, or III in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV protease, HIV growth, or both.
In another embodiment, the present invention provides novel compounds for use in therapy.
In another embodiment, the present invention provides he use of novel compounds for the manufacture of a medicament for the treatment of HIV infection.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that he compounds of the present invention contain symmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The present invention is intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
As used herein, xe2x80x9cHIV reverse transcriptase inhibitorxe2x80x9d is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, delavirdine (Pharmacia and Upjohn, U90152S), efavirenz (DuPont), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), HBY 1293 (Hoechst), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), and MEN 10979 (Menarini Farmaceutici).
As used herein, xe2x80x9cHIV protease inhibitorxe2x80x9d is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), palinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), tipranavir (Pharmacia and Upjohn, U-140690), DMP-450 (DuPont) and ABT-378.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced. xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
One diastereomer of a compound of Formula I may display superior activity compared with the other. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.